10 Adjuvant Treatments

10 Adjuvant Treatments
The Massachusetts General Hospital Handbook of Pain Management

Adjuvant Treatments

Robert S. Cluff

My heart aches, and a drowsy numbness pains
My senses, as though of hemlock I had drunk,
Or emptied some dull opiate to the drains
One minute past, and Lethe-ward had sunk.
—“Ode to a Nightingale,” John Keats, 1795–1821

I. General considerations
II. An evidence-based approach
III. Anticonvulsants

1. Indications

2. Clinical guidelines

3. Drug characteristics
IV. Local anesthetics
V. Corticosteroids
VI. Antispasmodics
VII. Clonidine
VIII. Topical agents
IX. Conclusion
Selected Reading

The opioids and the anti-inflammatory agents are the primary analgesics used in pain management. These drugs have the unique property of providing immediate (i.e., within minutes to hours) pain relief. The opioids are the only drugs indicated for the treatment of moderate to severe pain. The anti-inflammatory drugs are useful for the treatment of osteoarthritis and rheumatoid arthritis, as well as various mild to moderate acute and chronic pain conditions, and as adjuncts in the case of severe pain. The remaining categories of analgesic drugs, called adjuvant analgesics, have primary indications [U.S. Food and Drug Administration (FDA) approved] for non-pain diagnoses, their analgesic effects being secondary. These non-pain diagnoses include epilepsy, depression, and cardiac arrhythmia. Characteristically, the adjuvant drugs do not provide immediate pain relief; rather, their effects are noticeable only after days or weeks of therapy.
The many categories of drugs in the adjuvant class include the cyclic antidepressants, the selective serotonin reuptake inhibitors, the monoamine reuptake inhibitors, the sodium channel blockers, the GABAergics, the benzodiazepines, and the alpha adrenergics. This chapter will focus on the use of anticonvulsants, local anesthetics, corticosteroids, and antispasmodics in the treatment of chronic (including cancer) pain. The psychotropic medications are described in Chapter 11, and analgesics for headache are described in Chapter 28. A brief review of all the adjuvant analgesics is presented in Appendix VIII.
The decision to begin a particular analgesic medication for any patient involves many issues. Each decision is based partly on previous experience (e.g., previous success with mexiletine for peripheral neuropathy). The potential benefit of a drug must be weighed against its side effects. The patient should be made aware of evidence of the drug’s efficacy and should have realistic expectations for improvement. A check of the patient’s medical background is needed to identify any areas of susceptibility, and the patient’s current medications are reviewed for drug interactions.
Often, the side effects of an adjunctive agent are noticed within days of initiating treatment. However, the analgesic effect is often not apparent for 1 to 2 weeks. The possible utility, as well as the adverse side effects, should be considered, and appropriate patient selection is of key importance. For example, although the sedative effect of a tricyclic antidepressant can be utilized to improve sleep while treating pain, tricyclic use would be relatively contraindicated in an 80-year-old patient with Parkinson’s disease because of increased risk of falls, decreased cognitive capacity, and constipation.
Knowledge of a drug’s mechanism of action can direct treatment strategies if the cause of the pain is known (e.g., a sodium channel blocker in neuropathic pain). Over the past several years, the treatment algorithm for chronic pain has seen a shift toward a mechanism based approach. This concept is underscored in the following statement:
As we approach the new millennium, it is clear that we are on the brink of a major change in clinical pain management. We are poised to move from a treatment paradigm that has been almost entirely empirical to one that will be derived from an understanding of the actual mechanisms involved in the pathogenesis of pain. . . . The implications of this are immense and will necessitate major changes . . . to a mechanism-based classification. . . . The aim in the future will be to identify in individual patients what mechanisms are responsible for their pain and to target treatment specifically at those mechanisms. (Clifford Woolf, 1999)
This approach will make it possible to match a medication (with a known mechanism of action) to a pain syndrome in which this physiologic mechanism has been disrupted. The use of a sodium channel blocker in peripheral neuropathic pain is an example (upregulation of sodium channels with spontaneous activation). In addition, this approach will allow pairing of medications with different mechanisms of action to provide synergistic effects. Last, it will allow agents with the same mechanism of action to be used interchangeably, so that a drug that is effective but not tolerated because of side effects can be avoided.
Objective data from randomized controlled trials (RCTs) provide us with an evidence-based approach that is more scientific than relying on anecdotal reports. RCTs assess the efficacy of an agent versus a placebo or an established therapy. The best studies are those that include each of the following:

A homogeneous population

An established diagnosis with objective criteria (e.g., dermatomal scarring and sensory loss in postherpetic neuralgia)

An appropriate duration of treatment

Use of placebo
The use of homogeneous study populations enables mechanism based targeting of specific therapies. The number of subjects needed to show a statistical difference between the two study groups must be derived and used in the recruitment process. Table 1 presents a summary of adjuvant analgesics and the pain conditions for which they are effective, as demonstrated in RCTs.

Table 1. Adjuvant analgesic indicationsa

Despite the attractiveness of the mechanistic approach to both pain treatment and pain research, the literature is at present devoid of RCTs with outcome measures that distinguish between various pain qualities.
Postherpetic neuralgia, a devastating chronic pain entity, is ideally suited for mechanistic pain trials. This painful disease has a known cause, a preponderance of cases occurring in otherwise healthy people over the age of 60, and consistent symptomatology. Patients usually complain of one of three types of pain: (a) a constant deep aching or burning pain, (b) an intermittent spontaneous pain with a lancinating or jabbing quality, and (c) a dysesthetic pain provoked by light tactile stimulation (allodynia). The reduction of a distinct pain quality in response to a particular drug should allow more targeted treatment of specific pain types.
In a recent article, Max challenges the feasibility of this concept. He lists difficulties in this approach in both the clinical and the research arenas. Even so, he states that the concept deserves further attention, and he suggests a “coordinated approach by academic and industry pain scientists, FDA regulators of analgesics, and industry” to facilitate the research that is needed to make this concept a reality.
Anticonvulsants are a heterogeneous group of drugs used in the treatment of seizures, some of which have proven analgesic effect in pain patients. Anticonvulsants appear to benefit patients suffering from neuropathic pain–that is, pain related to direct injury of the peripheral or central nervous system. Six anticonvulsants are useful in neuropathic pain states–gabapentin, carbamazepine, valproic acid, clonazepam, phenytoin, and lamotrigine.
Gabapentin has quickly become widely used in the treatment of multiple pain syndromes, partly because of its lack of drug–drug interactions and mild side-effect profile. In 1998, data were presented from three multicenter placebo-controlled trials that demonstrated the efficacy of this drug in migraine headache, peripheral neuropathy, and postherpetic neuralgia. These findings demonstrate the utility of this agent in both neuropathic and non-neuropathic pain.
Although the mechanisms of action of the six anticonvulsants differ, the mechanisms underlying their anticonvulsant effect most likely contribute to their analgesic effect (e.g., the pathophysiology of epilepsy and neuropathic pain may be similar). Anticonvulsants have great side-effect potential, and their individual side-effect profiles are quite different, as described later (see also Appendix VIII).
1. Indications
The following are indications for anticonvulsants in patients with chronic pain:

Neuralgia–trigeminal, glossopharyngeal, and postherpetic

Neuralgia secondary to peripheral nervous system and central nervous system infiltration by cancer

Central pain states (e.g., thalamic pain syndrome and post-stroke pain)

Postsympathectomy pain

Post-traumatic neuralgia

Porphyria, Fabry’s disease, and others

Painful diabetic neuropathy

Paroxysmal pain in multiple sclerosis

Migraine headaches

Phantom limb pain and postamputation stump pain

Peripheral neuropathy secondary to a variety of disease states [e.g., alcoholism, amyloidosis, diabetes mellitus, human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), malabsorption]
2. Clinical guidelines
(i) Dosing regimens
Anticonvulsants are most effective in the management of paroxysmal lancinating dysesthesias associated with neuropathic pain syndromes; they are less useful for continuous neuropathic pain. Although carbamazepine is considered the drug of choice for the treatment of trigeminal neuralgia, its significant potential for side effects may limit its use to this indication and to the management of painful conditions refractory to other therapies.
In addition to a complete history and physical examination, a complete blood count and liver function baseline tests are recommended before starting an anticonvulsant.
A 4- to 6-week trial is the minimum required to adequately assess the analgesic efficacy of a new anticonvulsant. The patient is given dosage instructions along with a titration schedule. In general when beginning a new anticonvulsant analgesic, the phrase“Start low and go slow” is adhered to. This allows the body to adjust to the new drug and decreases the likelihood of significant side effects. Doses are generally increased until therapeutic effects or limiting adverse effects are observed, or until plasma concentrations approach toxic levels.
A review of previous analgesic drug trials is valuable, with special attention paid to pain relief and side effects. Serum levels do not appear to correlate well with pain response, but the potential for many side effects and toxicity mandates periodic evaluation of the serum level. Both physician and patient must understand that this process may take months to years (i.e., several medication trials).
(ii) Choice of drug
Because of its favorable side effect profile, gabapentin is often used as a first-line agent for various forms of neuropathic pain. Lamotrigine is a sodium channel blocker that may provide effective relief of chronic pain, but because of the risk of serious rash (including Stevens-Johnson syndrome), this agent is used only if other agents fail. A trial of carbamazepine or phenytoin is usually initiated prior to trials of valproic acid or clonazepam, because of superior controlled-trial and anecdotal support for the former two agents.
(iii) Initial dose and maintenance
As a general principle, a standard initial dose is chosen. The choice of a stable dose is determined by subsequent titration on the basis of serum levels, analgesic efficacy, and side effects. In some patients, attempts at tapering and discontinuation are successful, but often therapy is maintained at the therapeutic dose initially chosen. These medications should not be discontinued abruptly but should be tapered over a period of time to avoid withdrawal symptoms.
3. Drug characteristics
(i) Phenytoin
MECHANISM OF ACTION. Phenytoin is believed to have a stabilizing effect on neuronal membranes and can alter sodium, calcium, and potassium flux.
PHARMACOLOGY. Phenytoin has variable absorptions when administered orally. Its peak serum level is reached between 3 and 12 hours after the dose, but generally in 4 to 8 hours. It is highly protein bound and has approximately a 10% free fraction. This percentage varies with the serum protein level: low serum protein levels that are otherwise therapeutic might result in an elevated free fraction and toxicity. Metabolism is hepatic, with a serum half-life of approximately 24 hours.
RECOMMENDED DOSAGE. In an average adult patient, start with 100 mg three times a day (tid), check the blood level in 3 weeks, and follow the clinical response. A blood level over 20 µg/mL is considered to be toxic. Phenytoin should be taken after meals to avoid gastrointestinal (GI) irritation.
ADVERSE EFFECTS. Cerebellar–vestibular dysfunction, allergic reactions (skin rash), GI irritation, hepatotoxicity, and fetal hydantoin syndrome can occur with phenytoin. Folic acid deficiency can also occur, resulting in peripheral neuropathy and megaloblastic anemia. Other side effects include gingival hyperplasia (requiring meticulous oral hygiene) and hyperglycemia or glycosuria. These two side effects are related to fibrocyte stimulation and to phenytoin-induced inhibition of insulin secretion, respectively.
(ii) Carbamazepine
MECHANISM OF ACTION. Carbamazepine is chemically and pharmacologically related to the tricyclic antidepressants. It inhibits norepinephrine uptake, and it prevents repeated discharges in neurons. Carbamazepine most likely blocks sodium channels, as do phenytoin and lamotrigine. This observation is consistent with its ability to relieve lancinating pain in states of neuralgia.
PHARMACOLOGY. Carbamazepine is absorbed slowly and unpredictably after oral intake. Peak concentrations are seen in 2 to 8 hours. It is moderately protein bound and has active metabolites. Metabolism is hepatic, and excretion is urinary. It has a serum half-life of 10 to 20 hours, averaging 14 hours.
RECOMMENDED DOSAGE. Start at 200 mg/day and increase by 200 mg every 1 to 3 days to a maximum of 1,500 mg/day. If side effects are encountered, the dose should be decreased to the previous level for several days, and then gradually increased. Therapeutic doses usually range from 800 to 1,200 mg/day. Carbamazepine is a gastric irritant and therefore should be taken with food.
ADVERSE EFFECTS. Sedation, nausea, diplopia, and vertigo are the side effects that occur most frequently with this drug. Hematologic abnormalities such as aplastic anemia, agranulocytosis, pancytopenia, and thrombocytopenia can occur. Other side effects include jaundice (hepatocellular and cholestatic), oliguria, hypertension, and acute left ventricular heart failure.
Complete blood counts (CBCs) and liver function studies should be obtained. In general, CBCs are obtained at baseline, followed by every 2 weeks for a month, monthly for 3 months, twice over the following year, and then yearly. A patient who, in the course of treatment, exhibits low or decreased white blood cell or platelet counts should be monitored closely. Discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops. Liver function studies should always be obtained for patients with a history of liver dysfunction. Carbamazepine should be discontinued immediately in cases of aggravated liver dysfunction or acute liver disease.
(iii) Valproic acid
MECHANISM OF ACTION. Valproic acid is believed to increase the inhibitory activity of gamma-aminobutyric acid (GABA) through interference with GABA transaminase.
PHARMACOLOGY. Valproic acid has a rapid oral absorption, with peak concentrations in 1 to 4 hours. It is highly protein bound; it undergoes hepatic metabolism and is excreted renally. Its half-life is 10 to 12 hours in serum.
RECOMMENDED DOSAGE. Start at 15 mg/kg per day in divided doses. Increase weekly by 5 to 10 mg/kg per day until it becomes clinically therapeutic or the maximum dose of 60 mg/kg is reached. Baseline and periodic liver function tests are recommended because of previous reports of fatal hepatic failure. Reversible liver enzyme dysfunction occurs more commonly.
ADVERSE EFFECTS. GI symptoms such as nausea, vomiting, anorexia, and diarrhea can occur, but they improve with time. Sedation, tremors, and ataxia are occasionally seen, as are platelet aggregation effects. Hepatotoxicity can also occur.
(iv) Clonazepam
MECHANISM OF ACTION. Clonazepam is a benzodiazepine with anticonvulsant activity. It appears to act through enhancement of GABA inhibitory activity, which results in decreased firing of neurons.
PHARMACOLOGY. Clonazepam has good oral absorption, with a peak serum concentration in 1 to 4 hours. It is moderately protein bound; it undergoes hepatic metabolism to inactive metabolites and it is excreted renally. It has a serum half-life of approximately 24 hours.
RECOMMENDED DOSAGE. Start with 0.5 mg tid and increase by 0.5 mg every 3 to 4 days until an adequate response is achieved or a maximal dosage of 6 mg/day is attained. The usual therapeutic pain dosage range is 1 to 4 mg/day. Because of its sedative effect, clonazepam should be taken at bedtime.
ADVERSE EFFECTS. Lethargy and sedation, two common side effects, usually subside over time. Ataxia and dizziness are sometimes noted early in the course of drug therapy, but they improve with continued use.
Psychologic disinhibitory changes occur and are manifested as mood disturbances and delirium. A withdrawal syndrome, including seizures, can occur with abrupt discontinuation of therapy.
(v) Gabapentin
MECHANISM OF ACTION. The mechanism of analgesic effect for this drug is not known. Although this drug’s structure resembles that of the neurotransmitter GABA, it does not interact with GABA receptors, inhibit GABA degradation, or convert into GABA. It is believed that gabapentin increases the total brain concentration of GABA, but the mechanism of this effect is unknown. In addition, this drug binds to a calcium channel subunit that may play a role in analgesia.
PHARMACOLOGY. Gabapentin is not appreciably metabolized in humans. Its bioavailability is inversely proportional to dose, especially at low doses (e.g., 100 to 400 mg). At the recommended dosage schedule (300 to 600 mg, tid) the differences in bioavailability are not significant (average, about 60%). Food has no effect on the rate or extent of absorption. Gabapentin circulates largely unbound (<3% bound to plasma proteins). It is eliminated from the systemic circulation by renal excretion as unchanged drug. Elimination half-life is 5 to 7 hours, and this is unaltered by dose or following multiple doses. Plasma clearance is directly proportional to creatinine clearance.
RECOMMENDED DOSAGE. Start with a 300-mg capsule at bedtime for 1 to 2 days. If the bedtime dose is tolerated, begin three-times daily dosing. The dosage should be increased by 300-mg increments until either pain relief or intolerable side effects are experienced. If maximal three-times-daily dosing (900 mg tid) does not provide relief, four-times-daily dosing is a reasonable next step. Starting at 100 mg tid is appropriate in patients with a history of therapy failure as a result of intolerable side effects. Absorption of individual doses is dependent on GI enzymes and decreases abruptly at doses greater than 900 mg (excess gabapentin is eliminated in the stool). Dosage adjustments are required in patients with renal impairment (Table 2). Change in dose is not required in patients with hepatic insufficiency. When discontinuing the drug, it should be tapered gradually over at least 7 days.

Table 2. Neurontin dosage based on renal function

ADVERSE EFFECTS. Somnolence, dizziness, ataxia, fatigue, inability to concentrate, GI disturbances, and nystagmus are the most commonly observed adverse events with gabapentin treatment. Pedal edema is listed in one study as occurring in only 1.7% of subjects, although practitioners report that it is often responsible for drug termination.
(vi) Lamotrigine
MECHANISM OF ACTION. Lamotrigine (Lamictal) is an antiepileptic drug that is structurally unrelated to other drugs in current use. Lamotrigine acts by stabilizing the slow inactivated conformation of type IIa neuronal sodium channels, resulting in inhibition of repetitive firing of action potentials under conditions of sustained neuronal depolarization. No impairment of neuronal function occurs under normal firing conditions. By this mechanism, lamotrigine is believed to suppress the excessive release of excitatory amino acids (principally glutamate a neurotransmitter implicated in central sensitization and wind-up). By inhibiting the pathologic release of glutamate, lamotrigine has the potential to be antinociceptive and to prevent the mechanisms responsible for the establishment of chronic pain.
PHARMACOLOGY. Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailabilty, about 98%). The bioavailability is not affected by food. Peak plasma concentrations occur from 1.4 to 4.8 hours after drug administration. Data from in vitro studies indicate that lamotrigine is not highly protein bound, and therefore clinically significant interactions with other drugs through competition for protein binding sites are unlikely. Lamotrigine is metabolized by the liver through glucuronic acid conjugation.
RECOMMENDED DOSAGE. Because of an increased risk of rash (see the section “Adverse Effects”), dose escalation with lamotrigine is very gradual and should not exceed (at least initially) 50 mg in 2 weeks. It is advisable to start at 25 mg bid for 2 weeks and increase by 25-mg increments every 2 weeks until reaching 100 mg bid at week 6. After 2 weeks at 100 mg bid, it is reasonable to increase the dose by 25 mg bid weekly until the target dose of 200 mg bid is achieved. The recommended maximum dosage is between 400 and 500 mg/day divided into bid dosing.
ADVERSE EFFECTS. Dizziness, ataxia, somnolence, headache, diplopia, blurred vision, and nausea and vomiting are the most commonly observed side effects of lamotrigine. Although the incidence of rash is uncommon, it can be life threatening. The appearance of any systemic skin changes warrants evaluation by a physician, and lamotrigine should be immediately discontinued unless otherwise stated by that physician. Serious rash requiring hospitalization and discontinuation of lamotrigine, including Stevens-Johnson syndrome and toxic epidermal necrolysis, has occurred in association with lamotrigine therapy. Rare deaths have been reported, but these have been too few to permit a precise estimate of the rate.
The use of local anesthetics as blocking agents–subcutaneous, along the nerve roots, or at the spinal cord–is well known. However, the use of systemic local anesthetics as adjuvant analgesics is not as common. Intravenous lidocaine has been found to be useful in the treatment of some neuropathic pain conditions, including continuous and lancinating dysesthesias. Other conditions include neuropathic pain due to herpes zoster, phantom limb pain, diabetic neuropathy, and various other pain complaints resulting from neuropathies.
The mechanism of pain relief appears to be the stabilization of nerve membranes. This occurs as a result of the blockade of sodium channels, which prevents the influx of sodium. The rapid influx of sodium is responsible for the initiation and propagation of depolarization in nerve fibers, which may in turn be perceived as pain.
A trial of intravenous lidocaine is often used to assess (in a timely manner) the efficacy of sodium channel blockade in a particular chronic pain disease. Prior to the trial, a baseline electrocardiogram (ECG) and liver function tests should be obtained. Galer et al. demonstrated the value of the lidocaine infusion to achieve successful relief of pain with subsequent use of mexiletine, an oral sodium channel blocker.
The lidocaine infusion procedure involves administering 1 to 2 mg/kg of lidocaine intravenously over 10 to 15 minutes while the patient is adequately monitored. The dose is usually 100 mg for adult patients. Verbal analog scores are obtained before, during, and after the test. Patients commonly experience tinnitus, perioral numbness, a metallic taste in the mouth, and dizziness during the trial. A 50% or greater reduction in pain warrants a trial of mexiletine.
Mexiletine (Mexitil) has a favorable side-effect profile and is the most commonly used oral sodium channel blockers. Mexiletine is started at 150 mg at bedtime for about a week. If tolerated, it is increased to 150 mg tid. If pain relief is inadequate, the dose can be slowly escalated (every 5 to 7 days) to the maximum of 1,200 mg/day. This results in remarkable pain relief in some patients. Possible adverse effects include arrhythmias, syncope, hypotension, ataxia, tremors, nervousness, upper GI distress, dizziness, hepatotoxicity, skin rash, visual changes, and fever and chills.
Corticosteroids are useful as adjuvant analgesics, either alone or in combination with opioids. The exact mechanism of action is not clear. A peripheral effect is apparently the result of a reduction of inflammation, and a central effect may occur through altered neurotransmitter levels. In addition, corticosteroids are believed to reduce neuronal excitability by affecting cell membranes directly.
Steroids are used primarily in the management of pain resulting from rheumatic disease and cancer. They may reduce pain resulting from metastatic bone tumors, spinal cord compression, plexopathies, lymphedema, hepatomegaly, and some types of primary tumors. High doses of steroids can be tried for 1 week. If there is not a positive response, therapy should be terminated. If there is a useful therapeutic response, therapy should be continued but tapered to the lowest dosage that maintains the response. Prednisone (100 mg every day), methylprednisolone (100 mg every day), or prednisolone (7.5 mg every day) can be tried for 1 week and then tapered.
Steroid tapers (e.g., Medrol Dosepacks) are often useful in nonmalignant pain of acute onset (e.g., back pain) or for an exacerbation of a chronic pain state. The standard taper of oral methylprednisolone is from 24 to 0 mg over a period of 7 days.
The numerous adverse effects of steroids are well known and range from osteoporosis and infections to gastric ulcerations, perforations, and Cushing’s disease. These are not first-line medications, and explicit risk–benefit analysis should precede their administration. As a general principle, steroids should not be used in combination with the nonsteroidal anti-inflammatory drugs.
The two antispasmodic agents routinely used to treat chronic pain are lioresal (Baclofen) and cyclobenzaprine (Flexeril). Tizanidine (Zanaflex) is a relatively new agent with a mechanism of action similar to that of clonidine, an adjuvant analgesic often used in the treatment of sympathetically maintained pain.
(i) Baclofen
Baclofen is an antispasmodic drug that is often used in the treatment of spasticity associated with multiple sclerosis and spinal cord lesions. However, it is believed to possess some analgesic properties, which may augment opioid-induced analgesia. This apparently occurs through its GABA-B agonist actions. Baclofen appears to be useful in the treatment of painful spasticity, trigeminal neuralgia, and other forms of neuropathic pain, particularly lancinating pain. It should be avoided in patients with seizure disorders and impaired renal function.
Baclofen is usually started at 5 mg tid orally. Each dose can be increased by 5 mg every 3 days, to a maximum of 80 mg/day. Baclofen is also administered intrathecally, and pump systems are sometimes implanted for continuous infusion therapy in selected patients. Common side effects include drowsiness, fatigue, vertigo, orthostatic hypotension, headaches, hypotonia, psychiatric disturbances, insomnia, slurred speech, ataxia, rash, urinary frequency, and GI distress. These can be avoided through slow titration and avoidance of abrupt discontinuation.
(ii) Flexeril
Flexeril relieves muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm resulting from central nervous system disease. Flexeril is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Relief of muscle spasm results in relief of pain, tenderness, movement limitation, and activity restriction. Flexeril is closely related to the tricyclic antidepressants and its side-effect profile closely resembles that of the tricyclics. Common side effects are drowsiness, dry mouth, and dizziness. Tachycardia, hypertension, syncope, and GI upset have also been reported. Flexeril should not be used in conjunction with a monoamine oxidase inhibitor. Other contraindications are similar to those of the tricyclics and include cardiac arrhythmias, hyperthyroidism, and urinary obstructions. The usual dosage is 10 mg tid, with a range of 20 to 40 mg/day in divided doses. Flexeril use should not exceed 2 to 3 weeks.
(iii) Zanaflex
Zanaflex is an alpha-2-agonist that decreases sympathetic transmission at the level of the dorsal horn. Its antispasmodic action is attributed to reduced facilitation of the spinal motor neurons. Following oral administration, Zanaflex is completely absorbed. Its half-life is approximately 2.5 hours and its duration of action is short (3 to 5 hours). It is indicated for sympathetically maintained pain, as well as for pain described as lancinating, electrical, or burning. Adverse effects most commonly seen with use of Zanaflex include dry mouth, sedation, asthenia (weakness, fatigue, and/or tiredness), and dizziness. Dosage is started at 1 to 2 mg at bedtime, followed by 1 mg tid. The usual daily dose for chronic pain is 4 to 12 mg. Maximum dose should not exceed 36 mg/day.
Clonidine stimulates alpha adrenoreceptors in the brainstem, thereby decreasing sympathetic outflow from the central nervous system with a resultant decrease in peripheral resistance, heart rate, and blood pressure. Its unique mechanism of action explains why it is the only transdermal or oral agent that employs the mechanistic treatment approach for sympathetically maintained pain.
The transdermal patch (Catapres-TTS) is the preferred mode of administration, as it produces more consistent blood levels. Dosing with the patch starts with the TTS-1 and can increase to a maximum of two TTS-3 patches applied every 7 days. The patch should be applied to a hairless area of intact skin of the upper arm or chest. Subsequent patches should be applied to a different site and the prior one removed to prevent skin irritation. The most common adverse events include dry mouth, drowsiness, fatigue, headache, lethargy, and sedation. Dizziness is not uncommon, especially in those with low baseline blood pressures.
Disorders responsive to topical therapy include complex regional pain syndromes and peripheral polyneuropathy. Transdermal analgesic therapy is often used in patients who cannot tolerate oral administration irrespective of the pain condition (e.g., the Duragesic patch). Postherpetic neuralgia (PHN) is an ideal chronic pain syndrome to treat with topical agents for several reasons. Most PHN patients have clearly demarcated areas of affected skin, and they obtain relief of pain from modest amounts of a topical preparation and suffer few accompanying side effects.
Three categories of topical agents have received the most attention: capsaicin preparations, local anesthetics, and nonsteroidal anti-inflammatory drug preparations. All three have been demonstrated in controlled trials to be effective analgesics in PHN patients. Anecdotally, many drugs are being mixed into creams and ointments by compounding pharmacies for the treatment of superficial pain (e.g., ketoprofen, 100 mg/mL, plus bupivacaine, 50 mg/mL, plus ketamine 50 mg/mL). An endless number of mixtures could potentially be used. Combining agents that have different mechanisms of action may increase the likelihood of significant benefit. Use of these agents requires caution, however, as applying the mixture too often or to a large surface area may result in toxicity.
The adjuvant analgesics include a great number of drugs with various mechanisms of action. As the name implies, they were originally used as “add on” therapy, in combination with an opioid or an anti-inflammatory agent. Presently, they are often the first choice for analgesic therapy. Although little progress has been made in matching drug mechanism of action to pain pathophysiology, there has been some success anecdotally. For instance, although neuropathic pain appears to be resistant to pharmacologic treatment in general, certain drugs (e.g., sodium channel blockers) do seem to be effective. RCTs provide us with the best evidence available to determine treatment strategy. Treatment approaches need to be based on scientific evidence, yet each patient is unique; therefore, treatment needs to be adjusted to the individual. This is just one of the challenges faced when treating patients with chronic pain.

Benedetti C, Butler SH. Systemic analgesics. In: Bonica JJ, ed. The management of pain, vol. 2. Philadelphia: Lea & Febinger, 1990:1640–1675.

Galer BS, Harle J, Rowbotham MC. Response to intravenous lidocaine infusion predicts subsequent responses to oral mexiletine: A prospective study. J Pain Symptom Manage 1996;12:161–167.

Max MB. Is mechanism-based pain treatment attainable? Clinical trial issues. J Pain 2000;1(suppl 1):2–9.

McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for management of pain: A systematic review. Br Med J 1995;311: 1047–1052.

Munglani R, Hill RG; Other drugs including sympathetic blockers. In: Wall PD, Melzack R, eds. Textbook of pain, 4th ed. New York: Churchill-Livingstone, 2000:1233–1250.

Woolf CJ, Decosterd I. Implications of recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain 1999;82:1–7.


3 comments on “10 Adjuvant Treatments

  1. Tinnitus treatment varies dependent with the variety along with seriousness of your current tinnitus.

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